lung cancer patients and pulmonary embolism risk factors
Overview
Pulmonary embolism (PE) is a grave complication observed in individuals afflicted with lung cancer. This investigation aimed to ascertain the risk factors and evaluate the clinical attributes of advanced lung cancer patients who develop PE.
In this research, a retrospective assessment was conducted on patients admitted to our medical facilities from January 2020 to June 2022. The case group encompassed individuals with lung cancer and concomitant PE, while a control group, closely matched, was employed to pinpoint potential risk factors. The statistical analysis was executed utilizing the R programming language.
The study encompassed a total of 4957 patients, with 162 subjects (comprising 54 cases and 108 controls) forming the basis for this analysis. The prevalence of lung cancer accompanied by PE in the study population was calculated to be 1.08%. The majority of patients were of the male gender, and the most prevalent histological subtype was adenocarcinoma (constituting 67% of cases), followed by squamous cell carcinoma, small cell carcinoma, and poorly differentiated non-small cell lung cancer. Most patients exhibited a high performance status (PS) score, with 50% experiencing respiratory failure, primarily in the form of hypoxia, and 33% having comorbid deep vein thrombosis (DVT). A noteworthy 48% of patients were diagnosed with concurrent PE. Subsequent analysis demonstrated that the presence of PE was an independent predictor of unfavorable survival outcomes. Additionally, a PS score exceeding 1 emerged as an independent risk factor for PE development in lung cancer patients.
This study provides crucial insights into the epidemiology and prognosis of PE in lung cancer patients. It also highlights the significance of a poor Eastern Cooperative Oncology Group performance status (ECOG PS), an aspect not previously reported, as an independent risk factor for PE in this specific patient population.
Introduction
Pulmonary embolism (PE) is a life-threatening condition stemming from the obstruction of pulmonary arteries or their branches by emboli, often originating from detached deep venous thrombosis (DVT). It poses a significant health risk in Europe, with reported annual incidence rates reaching as high as 115 per 100,000 population. This ailment can lead to abrupt fatalities in some cases. Notably, individuals with cancer face an elevated risk of developing PE and experiencing more severe manifestations of the condition. The overall risk of venous thromboembolism (VTE), encompassing DVT and PE, in cancer patients is nearly seven times higher compared to those without malignancies.
Lung cancer, being one of the most prevalent cancers globally, stands out as the most susceptible to PE, accounting for a substantial 23.5% of PE cases in individuals with malignancies. Furthermore, lung cancer patients diagnosed with PE face a heightened risk of in-hospital mortality in comparison to those with PE and other types of cancer combined.
Previously published research indicates that a significant number of lung cancer patients with PE are diagnosed in advanced stages of the disease, with dyspnea being a common symptom. Various factors, including elevated D-dimer levels, chemotherapy, the presence of DVT, advanced TNM stage (III-IV), adenocarcinoma histology, ALK mutation, and positive PD-L1 expression, have been associated with an increased risk of PE in lung cancer patients. However, these studies often had limitations, such as small sample sizes, absence of control groups, or being conducted across different cancer types. Consequently, there remains an unmet need to comprehensively elucidate the characteristics and risk factors specific to lung cancer patients with PE.
Methods
This retrospective study was conducted across two medical centers and adhered to the guidelines outlined in the STROBE statement.
The study’s focus was on patients admitted to our hospitals between January 2020 and June 2022, who had received a diagnosis of lung cancer. Inclusion in the case group necessitated meeting specific criteria: (1) lung cancer diagnosis confirmed through pathological examination and (2) pulmonary embolism (PE) diagnosis confirmed by at least two radiologists via contrast-enhanced chest CT or CT pulmonary angiogram (CTPA). Patients with clinically suspected PE or lung cancer were excluded from the study. In cases where multiple admissions satisfied these criteria, preference was given to the patient’s initial hospitalization. For each identified case, two control patients without PE were selected and matched in terms of age, gender, whether it was the patient’s first admission for lung cancer or not, and admission date (within a 1-year window), in order to identify potential risk factors.
The study gathered a comprehensive set of clinical data, which encompassed the following categories:
- Demographic and baseline information, including age, gender, body mass index (BMI), histological type of lung cancer, smoking history, prophylactic anticoagulation, and presenting symptoms.
- Results of blood tests, including arterial blood gas analysis, biochemical parameters, complete blood count, D-dimer levels, serum carcinoembryonic antigen (CEA), serum cytokeratin 19 (also known as CYFRA 21-1), and serum neuron-specific enolase (NSE).
- Data from various diagnostic tests and examinations, such as ultrasound scans, CT scans, and electrocardiograms.
- Information pertaining to treatment modalities, encompassing anticoagulation therapy, the utilization of central venous catheterization, and the administration of chemotherapy, antiangiogenic therapy, or immunotherapy.
- Prognostic data, particularly focused on the resolution of PE as detected by contrast-enhanced chest CT or CTPA, as well as the overall survival (OS) of the patients.
For patients with PE during their initial admission, the data was collected prior to commencing treatment. For those who developed PE during the follow-up period for their lung cancer, data was gathered before or at the time of the initial PE diagnosis. Survival data for the study participants were collected via telephone follow-up, which began 2 months after the patient’s discharge and continued at 2-month intervals thereafter. The final follow-up took place on December 31, 2022.
Statistical Analysis
Statistical analyses were performed using either R (version 4.1.1) or SPSS (version 22.0). Frequency and proportion were employed to report categorical data, with hypothesis testing conducted using the chi-square test. Continuous variables were presented as either mean and standard deviation (SD) or median and interquartile range, and their statistical significance was assessed using t-tests or Wilcoxon signed rank tests, as appropriate.
Survival characteristics were graphically represented through Kaplan-Meier curves, and associations between variables and survival were assessed and adjusted using Cox regression analysis. Given the limitations of a relatively small sample size, only variables widely recognized as factors or those demonstrating a p-value of no more than 0.05 in univariate conditional logistic regression analysis were considered for inclusion in multivariate conditional logistic regression models when investigating the risk factors associated with lung cancer accompanied by PE. A p-value of less than 0.05 was employed to indicate statistical significance in the analyses.
Results
A comprehensive review of 4957 patients diagnosed with lung cancer was conducted. Among them, 57 patients with pulmonary embolism (PE) were initially selected for further evaluation, ultimately resulting in 54 patients (approximately 1.08%) forming the case group. Correspondingly, 108 patients with lung cancer but without PE were meticulously matched and included in the control group, as outlined previously in the study flow.
The cases in the study displayed an average age of 67 years with a standard deviation of 10 years. Their mean body mass index (BMI) was 22.80 kg/m² with a standard deviation of 2.54 kg/m². Importantly, all the cases were diagnosed at an advanced TNM stage (III-IV). The majority of patients in the case group were male, constituting approximately 67% of the population, while roughly 46% of the cases were either current smokers or ex-smokers. Adenocarcinoma emerged as the most prevalent pathological type, accounting for 67% of cases, followed by squamous carcinoma (22%), small cell carcinoma (7.4%), and poorly differentiated cancer (3.7%). A substantial portion of the cases (52%) presented with an Eastern Cooperative Oncology Group performance status (ECOG PS) score equal to or greater than 2, and 39% had comorbid chronic airway diseases, including chronic obstructive pulmonary disease (COPD), asthma, or bronchiectasis.
At the time of lung cancer diagnosis, nearly half of the cases (48%) were concomitantly diagnosed with PE. Among these cases, the predominant symptoms were cough (65.4%) and dyspnea (65.4%). Other reported symptoms included expectoration (34.6%), chest pain (19.2%), and bloody phlegm (7.6%). Only one patient in this subgroup was asymptomatic, with PE incidentally identified during routine enhanced CT scanning. Additionally, 28 patients developed PE during the follow-up period, with a median time to diagnosis of 14 months. Dyspnea was the primary symptom in the majority of these cases (67.8%), while a smaller subset presented with confusion (14.3%), and some were asymptomatic (10.7%).
In this study, 54 out of a total of 4957 lung cancer patients (approximately 1.08%) were identified with pulmonary embolism (PE). These patients had a mean age of 67 years and a mean BMI of 22.80 kg/m². Notably, all of them were diagnosed at an advanced TNM stage (III-IV), with the majority being male (67%) and approximately 46% having a history of smoking. Adenocarcinoma was the most common pathological type (67%), followed by squamous carcinoma (22%), small cell carcinoma (7.4%), and poorly differentiated cancer (3.7%). Over half of the patients (52%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 2 or higher, and 39% had chronic airway diseases, such as chronic obstructive pulmonary disease (COPD), asthma, or bronchiectasis.
A subset of these patients underwent arterial blood gas analysis, revealing that half of them (50%) experienced respiratory failure. Among those with respiratory failure, 16 had hypoxic respiratory failure, while one exhibited hypoxemia and hypercapnia. Nine patients had elevated lactic acid levels. In the subgroup with respiratory failure, eight were classified as having intermediate-risk PE.
For non-small cell lung cancer (NSCLC) patients, 35 of 50 cases underwent next-generation sequencing (NGS) analysis, identifying common mutations in the EGFR and ALK genes in 13 and 3 cases, respectively, with no ROS1 mutations found.
Blood tests in the case group revealed elevated tumor markers, including CEA, CYFRA 21-1, and NSE in a subset of patients. Additionally, NT-proBNP and troponin T (TnT) tests indicated elevated levels in some cases. Doppler ultrasonography of the lower extremities revealed deep vein thrombosis (DVT) in 34.2% of patients and superficial vein thrombus in 23.6%. A cardiac echocardiogram indicated pulmonary hypertension in 11 cases, and six cases displayed an acute dilated right atrium and/or ventricle. Electrocardiograms (ECG) showed various abnormalities in some patients.
Treatment-wise, most patients received anticoagulant therapy, and thrombolytic therapy was not administered. During hospitalization, 12 patients passed away, while 42 were discharged following symptom improvement and were prescribed oral anticoagulants. The study found that anticoagulation therapy was effective in several cases, with the removal or shrinkage of emboli observed during follow-up.
To assess the impact of PE on the survival of lung cancer patients, a control group of 108 patients without PE was included. The results showed that patients with PE had significantly shorter median survival than those without PE, with univariate and multivariate analyses confirming PE as an independent prognostic factor.
The study also investigated the risk factors for lung cancer with PE, finding that a high ECOG PS score (PS > 1) was the only significant independent risk factor. Other variables, including smoking history, BMI, treatment-related factors, and various blood markers, were associated with varying odds of developing PE but were not identified as independent risk factors in the multivariate analysis.
Conclusion
The primary cause of pulmonary embolism (PE) in this study was deep vein thrombosis (DVT), aligning with the established concept of Virchow’s Triad, which encompasses factors such as blood flow stagnation, endothelial injury, and hypercoagulability. Malignant tumors, including lung cancer, are known to trigger the release of cytokines from immune cells while simultaneously releasing fibrinolytic inhibitors, ultimately fostering a state of hypercoagulability. Furthermore, tumor cells can directly invade blood vessels, inflict damage to the endothelium, and consequently lead to thrombus formation.
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This study undertook a thorough examination of lung cancer cases complicated by PE in a specific region. Notably, it was not uncommon for patients to present with PE concurrently at the time of their initial lung cancer diagnosis. Additionally, a noteworthy finding in this study was the identification of a poor Eastern Cooperative Oncology Group performance status (ECOG PS) as an independent risk factor for PE, which had not been previously reported.
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The study’s diagnostic process involved the routine use of enhanced CT scans for biopsy specimens and TNM staging in patients suspected of having lung cancer. This approach enabled the accurate detection of PE in lung cancer patients. The prevalence of PE in lung cancer patients in this study was determined to be 1.08%, slightly higher than reported in some prior studies. This variation could be attributed to the racial composition of the study population and the higher proportion of patients with advanced TNM stages.
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